Apolipoprotein E–Promoter Single-Nucleotide Polymorphisms Affect the Phenotype of Primary Open-Angle Glaucoma and Demonstrate Interaction with the Myocilin Gene

Copin, Bruno; Brézin, Antoine P.; Valtot, F; Dascotte, J C; Béchetoille, A; Garchon, Henri‐Jean

doi:10.1086/340733

Cited by 95 publications

(44 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apolipoprotein E (APOE), which is associated with Alzheimer disease, was reported to also modify the glaucoma phenotype. A promoter polymorphism was associated with increased optic nerve damage, while other polymorphisms interacted with a glaucoma gene; MYOC polymorphism tends to increase the IOP in POAG patients (Copin et al 2002). The APOEε 3 and APOEε 4 (Vickers et al 2002) alleles are associated with elevated risk for glaucomatous changes.…”

Section: Other Glaucoma Associated Genesmentioning

confidence: 99%

Genetic Bases for Glaucoma

Fuse

2010

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Glaucoma is a complex, heterogeneous disease characterized by a progressive degeneration of the retinal ganglion cells (RGCs) and their axons in specific regions of the retina. The loss of the RGCs and their axons results in visual field defects in the areas corresponding to the RGC degeneration. Glaucoma is the second highest cause of blindness worldwide affecting approximately 70 million people (Quigley 1996). Primary open angle glaucoma (POAG; MIM 137760), the most common type of glaucoma in most populations, is an ocular disease in which the intraocular pressure (IOP) is consistently elevated above 22 mm Hg (Quigley 1993). The POAG patients who have an IOP within the normal range of < 22 mmHg, are classified as having normal tension glaucoma (NTG) (Werner 1996). The prevalence of NTG is significantly higher in the Japanese than in Caucasians (Shiose et al. 1991). The Tajimi study, a population-based cross-sectional study, reported that glaucoma is a major cause of blindness in the Japanese, and that NTG has an overall prevalence of 3.60% (Iwase et al. 2004). Approximately 90% of Japanese POAG patients have NTG which is significantly higher than that in Caucasians. Both POAG and NTG have optic nerve damage, but the mechanism leading to the death of the axons of the RGCs in the optic nerve has still not been completely determined.Although the precise molecular basis of glaucoma has also not been completely established, it is most likely a genetically heterogeneous disorder resulting from the interaction of multiple genes and environmental factors (Fig. 1) (Raymond 1997;Sarfarazi 1997). Family history, systemic hypertension, diabetes, and cigarette smoking have been shown to be risk factors for glaucoma. The life-time risk of glaucoma in relatives of patients with glaucoma is 22.0% while it was 2.3% in relatives of non-glaucomatous controls yielding a risk ratio for glaucoma of 9.2 (Wolfs et al. 1998).The association of diabetes mellitus and cigarette smoking with POAG is still controversial. However, a recent meta-analysis supported a significant association of diabetes mellitus with POAG with an odds ratio (OR) of 1.50 assuming random effects (Bonovas et al. 2004b). For current smokers, another meta-analysis found that the OR for a fixed-effects model was 1.37 (Bonovas et al. 2004a).

show abstract

Section: Other Glaucoma Associated Genesmentioning

confidence: 99%

Genetic Bases for Glaucoma

Fuse

2010

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

show abstract

“…Some investigators suggest that MYOC promoter variants may influence the progression of glaucoma (10,11,29), while others disagree with this conclusion (2). Since human patients are currently offered genetic testing based on the presence of noncoding variants, the issue is very important.…”

mentioning

confidence: 99%

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

Gould

Miceli-Libby

Savinova

et al. 2004

Molecular and Cellular Biology

120

View full text Add to dashboard Cite

Glaucoma is a leading cause of preventable blindness in the world (30,46). Elevated intraocular pressure (IOP) is one of the strongest known risk factors (41) and can cause glaucoma in animal models (6). IOP elevation in human glaucoma results from increased resistance to aqueous-humor drainage (36). Although the etiology of glaucoma is complex, the result is death of retinal ganglion cells and loss of vision (31). Primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States and affects up to 1 to 2% of people over 40 years of age (47).Multiple genetic loci are reported to contribute to POAG (32,34,42,49,51,52). Disease-associated mutations have been identified in the myocilin gene, MYOC (14, 43). Studies from a broad range of ethnic backgrounds generally agree that MYOC mutations are responsible for approximately 3% of adult-onset POAG and a greater proportion of juvenile-onset open-angle glaucoma (2, 14). Despite this, neither the normal function(s) of MYOC nor how MYOC mutations result in IOP elevation and glaucoma has been defined.MYOC has also been implicated in steroid-induced ocular hypertension with glaucoma. Steroid-induced ocular hypertension in response to glucocorticoid treatment occurs in as many as 40% of people treated with glucocorticoids (37, 53). MYOC is up regulated in cultured trabecular meshwork (TM; an ocular drainage structure) cells treated with glucocorticoids.Thus, MYOC was identified as a candidate to mediate glucocorticoid-induced glaucoma (26,28). Supporting this, IOP elevation (assessed as an increase in drainage structure resistance) is glucocorticoid inducible in some but not all human anterior segment perfusion cultured eyes. In these cultures, IOP elevation correlates with MYOC induction (8) and ultrastructural changes (9) in the TM. Cultured anterior segments that developed elevated IOP had MYOC induction, while those that did not develop elevated IOP had no MYOC induction (8). Similarly, monkeys treated with glucocorticoids develop ocular hypertension (13), and in at least some eyes glucocorticoids induce MYOC and cause ultrastructural changes in the TM (8).Further studies, which do not involve steroid use, also can support a role for elevated MYOC levels in IOP elevation and glaucoma. In some glaucoma patients, the TM has elevated MYOC levels and broadened MYOC distribution (24). Cultured human anterior segments perfused with recombinant MYOC are reported to develop elevated IOP, whereas those perfused with an equal amount of other proteins or denatured MYOC do not (12). Finally, in the albino Wistar rat strain, experimental IOP elevation did not induce ocular MYOC, suggesting that MYOC induction does not occur secondary to IOP elevation (1).Despite these circumstantial data, there is no direct in vivo evidence that elevated MYOC levels cause IOP elevation and glaucoma. The rat study mentioned above (1) does not exclude MYOC elevation as a secondary response to increased IOP in different settings (either in different genetic contexts or in respo...

show abstract

“…[51][52][53][54][55][56][57] Although these are generally assumed to be connected via a common pathway of neuronal degeneration, it is intriguing to postulate that the underlying causes of some forms of these insidious diseases of aging might be via common or related effects within the outflow pathway. Consistent with this possibility, the JCTM cells showed relative overexpression of microtubuleassociated t protein, a constituent of neurofibrillary tangles.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Genes in Cells Cultured from Juxtacanalicular Trabecular Meshwork and Schlemm's Canal

Wang

Ying

Yue

2014

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Purpose: The purpose of this study was to distinguish differences in gene expression between cells cultured from the juxtacanalicular trabecular meshwork ( JCTM) and those from Schlemm's canal (SC), to gain clues to differences between those cell types, and to add to our baseline knowledge of gene expression differences in these cell types for later comparison between cells from nonprimary open-angle glaucoma (POAG) and POAG outflow tissues. Methods: A set of JCTM and SC cells was cultured from each of 2 donor eyes by an explant method, grown to passage 3, and frozen in liquid nitrogen. The cells were thawed, total RNA was extracted, and the probes made from total RNAs were hybridized to MICROMAX human cDNA microarray slides in 2 separate trials. Differentially expressed genes were analyzed using PubMed, Prosite, and IPA software, and the expression of several of the genes including intercellular adhesion molecule-1 (ICAM-1), tenascin, and b-spectrin was assessed by immunofluorescence. Results: Schlemm's canal cells differentially expressed ICAM-1, spectrin, complement, fibulin-1, and several genes consistent with an endothelial origin in both arrays, while the JCTM cells more often overexpressed genes consistent with contractile, matrix function, and neural character. At the same time, many genes highly expressed in the first array were not highly overexpressed in the second. One highly overexpressed gene in the JCTM in both arrays, that for heparan sulfate 3-O-sulfotransferase-1 precursor, is thought to be somewhat unique, and could affect the glycosaminoglycan functionality in the extracellular matrix (ECM). Conclusions: We found generally good agreement between the 2 array trials, but some contradictions as well. Many of the genes overexpressed in each cell type had been described in earlier work, but several were new. Tables of genes, grouped by cellular function, and the complete datasets are provided for the development of new hypotheses.

show abstract

Apolipoprotein E–Promoter Single-Nucleotide Polymorphisms Affect the Phenotype of Primary Open-Angle Glaucoma and Demonstrate Interaction with the Myocilin Gene

Cited by 95 publications

References 32 publications

Genetic Bases for Glaucoma

Genetic Bases for Glaucoma

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

Differential Expression of Genes in Cells Cultured from Juxtacanalicular Trabecular Meshwork and Schlemm's Canal

Contact Info

Product

Resources

About